Schizophrenic individuals show abnormalities in event related potentials (ERPs) and in the gamma and[unreadable] theta frequency components of these ERPs. Marked abnormalities occur in gamma and theta oscillations[unreadable] elicited by novel or deviant (unpredicted) stimuli. The goal of this project is to investigate, using detailed[unreadable] computer simulations, how these gamma, theta, and ERP abnormalities may arise from cellular and synaptic[unreadable] pathology in cortex. Recent studies have uncovered basic mechanisms by which gamma and theta[unreadable] oscillations are generated in cortex?both gamma and theta arise from the same cortical microcircuit[unreadable] involving pyramidal cells and two types of interneurons. Each cell type plays a different role in generating[unreadable] gamma vs. theta. Based on data from the literature, and findings from Subprojects 0007, 0008, and 0009, we will develop a[unreadable] detailed biophysical level simulation of this microcircuit, and we will examine the circuit mechanisms that[unreadable] underlie robust generation of theta and gamma, particularly the role of dendritic gap junctions. We[unreadable] hypothesize that synaptic facilitation and depression, in celltype specific connections, alters the balance[unreadable] between gamma and theta; thus, abnormalities in short-term plasticity may underlie the excess gamma and[unreadable] decreased theta seen in schizophrenic patients. We propose a specific circuit model for how the cortex[unreadable] responds to novel versus familiar stimuli?the circuit involves known connections between cortical layers III[unreadable] and V. Glutamtatergic dysfunction, as reported in schizophrenia, will lead to predicted failures in this novelty[unreadable] detection mechanism, and to associated abnormalities in gamma oscillations and the mismatch negativity in[unreadable] the ERP. We focus on understanding the NMDA antagonist actions of ketamine, which produces[unreadable] gamma/theta abnormalities similar to those in schizophrenia, and which is known to induce disassociative[unreadable] symptoms. We hypothesize that phenytoin, which blocks persistent sodium channels, will reverse the[unreadable] gamma and theta abnormalities induced by ketamine, and also possibly in animal and human models.[unreadable] Perception, cognition, and memory are associated with specific electrical signatures in the brain?[unreadable] oscillations of cell firing at low (theta) and high (gamma) frequencies. We will investigate how these[unreadable] oscillations are generated by specific circuits in the cerebral cortex, and how abnormalities in synaptic[unreadable] signaling reported in schizophrenic brains give rise to these altered oscillations. This understanding may[unreadable] lead to insight into how schizophrenia affects cognitive processes, and to the cellular mechanisms[unreadable] responsible for the symptoms of the disease.[unreadable]